The traditional model of the development of end-stage renal disease (ESRD) in type 1 diabetes (T1DM), in which microalbuminuria (MA) leads to proteinuria and then proteinuria is followed by renal function loss, has been challenged recently. Increase in urinary albumin excretion is an important determinant of diabetic nephropathy progression, but it does not entirely explain this phenomenon. For example, the loss of renal function commences earlier than previously recognized and precedes the onset of proteinuria (Perkins et al., J Am Soc Nephrol. 18:1353-1361, 2007). A longitudinal study of T1DM (the 1st Joslin Study of Natural History of Microalbuminuria) showed that renal function decline began with the onset of MA in about one third of patients and progressed in a linear fashion from normal kidney function to renal insufficiency (Perkins et al., 2007, supra). In addition, renal function decline occurred in a noticeable proportion of patients with T1DM and normal albumin excretion (Perkins et al., 2007, supra; Caramori et al., Diabetes 52:1036-1040, 2003).